WO1987002359A1 - Aminoalcools de dihydrobenzothiophene et de thiochromane - Google Patents

Aminoalcools de dihydrobenzothiophene et de thiochromane Download PDF

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Publication number
WO1987002359A1
WO1987002359A1 PCT/EP1986/000607 EP8600607W WO8702359A1 WO 1987002359 A1 WO1987002359 A1 WO 1987002359A1 EP 8600607 W EP8600607 W EP 8600607W WO 8702359 A1 WO8702359 A1 WO 8702359A1
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WO
WIPO (PCT)
Prior art keywords
threo
group
oxo
hydrogen
propanol
Prior art date
Application number
PCT/EP1986/000607
Other languages
English (en)
Inventor
Ciampaolo Picciola
Mario Riva
Pier Giuseppe De Meglio
Piergiorgio Gentili
Original Assignee
Maggioni-Winthrop S.P.A.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from GB858525256A external-priority patent/GB8525256D0/en
Priority claimed from GB868615562A external-priority patent/GB8615562D0/en
Application filed by Maggioni-Winthrop S.P.A. filed Critical Maggioni-Winthrop S.P.A.
Publication of WO1987002359A1 publication Critical patent/WO1987002359A1/fr
Priority to DK297887A priority Critical patent/DK297887A/da
Priority to NO872468A priority patent/NO872468L/no
Priority to KR870700499A priority patent/KR870700621A/ko

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D335/00—Heterocyclic compounds containing six-membered rings having one sulfur atom as the only ring hetero atom
    • C07D335/04—Heterocyclic compounds containing six-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D335/06—Benzothiopyrans; Hydrogenated benzothiopyrans
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings

Definitions

  • This invention is concerned with new pharmacologically active compounds. More particularly, the compounds with which this invention is concerned are dihydrobenzothiophene and thiochromane aminoalcohols of the formula
  • R and R 1 represent hydrogen or a lower alkyl group, n represents an integer selected from 1 and 2, and R 2 represents a divalent radical selected from a)
  • A is a group selected from
  • R 4 represents a lower alkyl group
  • W represents hydrogen, a 2-furoyl radical or a group
  • Z represents a hydrogen, halogen or a lower alkyl or alkoxy group and m is an integer from 1 to 3, and their salts with inorganic acids, organic acids, cationic exchange resins and complexes with cyclodextrins.
  • the compounds of formula I in which R 1 does not represent hydrogen possess two structural asymmetry centers at the carbon atoms of the aliphatic side chain to which the hydroxy and the basic nitrogenated group are attached.
  • the compounds may therefore exist in threo and erythro stereoisomeric forms.
  • a mixture of the two stereoisomeric forms is formed as a result of the reaction, and it will be necessary to carry out an appropriate separation in order to get the desired form in a satisfactory pure condition.
  • the process for preparing the compounds of the foregoing formula I consists in reacting approximately equimolecular amounts of an alpha haloketone of formula II and a secondary amine of formula III, preferably in the presence of a proton acceptor in a solvent, thus obtaining the amino ketone of formula IV.
  • This latter is eventually hydrogenated to give compound I, either as a mixture of threo and erythro steroisomers, or as one single steroisomer, depending on the selected reaction conditions. If a mixture of diastereoisomers is obtained, then a separation into the two steric forms will have to be carried out in order to get them in a pure condition.
  • the reaction between compounds II and III is best carried out in a solvent of the classes comprising lower aliphatic alkanols, such as methanol, ethanol, propanol, isopropanol, butanol and the like; lower aliphatic ketones, such as acetone, methyl ethyl ketone and the like; acetonitrile; di-lower alkyl-formamides, such as dimethylformamide; aromatic hydrocarbons such as benzene, toluene, xylene and the like.
  • the reaction temperature is usually between the room temperature and the boiling temperature of the solvent.
  • the proton acceptor in the reaction between compound II and III may be any basic substance not interfering with the reaction.
  • inorganic substances are employed, most commonly alkali and alkaline earth carbonates and bicarbonates. Particularly effective were found to be sodium carbonate and sodium bicarbonate.
  • tertiary amines may be useful, and in some instances an excess of the amine III may give practical results.
  • the reaction time may range between wide limits. It has been found that a reaction time between 6 and 30 hours is appropriate, with limits between 6 and 24 hours being preferred.
  • Hydrogenation of compound IV to give the compounds of the present invention is best effected using a metal hydride, such as sodium borohydride or lithium aluminum hydride, in a solvent not interfering with the hydride and generally with the hydrogenation reaction.
  • the temperature may range between about -15° and 20°, preferably between about 0°C and 10°C, during the addition of the hydrogenating agent. The same temperature limits may be used if it is preferred to add a solution of the amino ketone to the hydrogenating agent dissolved or suspended in an appropriate solvent.
  • the reaction mixture is kept for some time, preferably 2-6 hours, at a temperature ranging between the room temperature and the boiling temperature of the solvent.
  • one of the forms may precipitate from the reaction solvent at the end of the hydrogenation step, the other remaining dissolved being in turn precipitated from the solvent, after filtering off the solids, by the addition of a hydrogen halide, such as hydrogen chloride, to the solvent, and isolating the diastereoisomeric form as the hydrohalogenide, usually the hydrochloride or the hydrobromide.
  • a hydrogen halide such as hydrogen chloride
  • Another common separation technique is chromatography, particularly dry column chromatography.
  • the products of this invention both those of the formulas I and IV above, show anti-hypertensive, platelet aggregation inhibiting, antithrombotic, hypolipemic, antianoxic, spasmolytic, calcium antagonizing and neuroleptic activity.
  • the anti-hypertensive activity was tested on groups of 5 SH rats (spontaneously hypertensive rats) and 5 DOCA rats (deoxycorticosterone acetate and sodium chloride loaded rats) weighing 200+10g, fasting from 18 hrs and treated orally with the invention compounds suspended in 0.5% gum arabic.
  • Table 1 shows that the tested compounds are endowed with good anti-hypertensive activity at all tested doses.
  • PHE phenylephrine
  • mice CrI:CD 1(CR) BR were treated orally with vehicle (controls) and with various doses of the compounds. After 2 hrs 14.5 mg/kg of 1-adrenaline was administered intraperitoneally and mortality was recorded after 24 hrs; in controls mortality was 100%. From log-dose-% protection curves the 50% protective doses were calculated ( Litchfield et al., J. Pharmacol. Exp. Ther. 96, 99, 1949).
  • Table 2 gives the results obtained with some of the compounds as compared with known drugs.
  • the new compounds generally show an activity higher than Tibalosine and Fentolamine.
  • MG 16311 was equivalent to Prazosin.
  • the receptor binding assay for the inhibition of 3 H-Prazosin, 3 H-Clonidine and 3 H-Spiperone binding to rat brain membrane was carried out according to Greenberg et al., Life Sci. 19, 69, 1976, and U'Prichard et al., Molec. Pharmacol. 13, 454, 1977.
  • Platelet aggregation was stimulated with collagen (2-4 mcg/ml) added simultaneously to PRP of control and treated rats. The results were assessed photometrically. Each test was replicated 4 times in groups of 3 animals. Aggregation curves were evaluated in terms of two parameters namely maximum optical density variation (maximum aggregation) and aggregation rate.
  • Table 4 gives the effects recorded after treatment with some of the tested compounds. They show an activity comparable to Ticlopidine and Suloctidil and only slightly lower than Dipiridamol.
  • Sprague Dawley Nos male rats (180-200 g) were treated orally for 4 consecutive days with vehicle (0.5 ml/100 g gum arabic 2.5%, controls) and with 1-2 doses of the tested compounds, and were sacrificed at the 5th day after 18 hrs fasting.
  • Total cholesterol (CHOL), triglycerides (TG), HDL cholesterol (CHOL-HDL) were assayed in secum and the liver was weighed.
  • MG 16444 and MG 16445 cause a dose-dependant, marked decrease both of CHOL and TG while MG 16311, MG 16426 and MG 16448 decrease TG and increase CHOL-HDL. Except for MG 16426, the liver weight is not affected. Their activity is higher than Clofibrate which, as known, causes a significative liver increase. The Probucol activity is moderate and is noted only after prolonged treatment (8 days).
  • MG 16311 and MG 16426 decrease the hyperlipemic effect caused by Triton WR 1339 (Moss et al., Antihyperlipidemic agents, from “Screening Methods in Pharmacology", Vol. II, page 136, Academic Press, 1971) lowering serum levels of CHOL and TG.
  • MG 16444 and MG 16445 inhibit hypertriglyceridemia from ethanol resp. by 60.8% and 78.5% at the oral dosis of 0.37 mM/kg..
  • the anti-hypoxic activity was determined according to Yasuda et al., Arch. Int. Pharmacodyn. 233, 136, 1978.
  • mice Groups of 10 male mice (21-23 g) were treated orally with vehicle (controls) and the invention compounds. After 45 or 90 minutes the animals were decapitated and the gasping time was determined. Table 6 gives the results obtained after administration of some of the invention compounds which display an activity higher than Suloctidil.
  • the oral acute toxicity in male mice of the invention compounds is very low.
  • the LD 50 is higher than 500 mg/kg for
  • MG 16444 and MG 16445 higher than 1,000 mg/kg for MG 16426 and 16448, and higher than 2,000 mg/kg for MG 16302, MG 16294, MG 16287, MG 16310, MG 16313 and MG 16298.
  • the threo isomer is obtained in a 35% yield and analyzes exactly like the identical compound of Example 1.
  • the erythro isomer is obtained in a 28% yield and has m.p. 201- -203°C (ethanol).
  • EXAMPLE 9 The threo-form of the compound of Example 1 (MG 16270) is prepared by the following alternative process.
  • Example 12 The two stereoisomers of Example 12 are prepared by an alternate route which is described in the following.
  • the threo isomer is obtained in 20% yield by a single recrystallization of the residue obtained by evaporation of the mother liquor from the recrystallization of the erythro isomer and extracting with ethyl acetate the mother liquor of the reaction.
  • M.p. 143-145°C ethanol; water 70:30).
  • Example 29 By the procedure of Example 29, and starting from 6-(alpha-bromoacetyl)-thiochromane and 4-(2-oxo-1-benzimidazolinyl)-piperidine, the corresponding aminoketone is obtained in 38% yield (MG 16413), m.p. 184-186°C, which is then reduced with NaBH 4 .
  • the intermediate aminoketone (MG 16448; m.p. 187-191°C) is prepared from 6-(alpha-bromopropionyl)-thiochromane (in turn prepared according to the procedure of Example 29 for the bromoacetyl homologue) and 4-(2-oxo-5-chloro-1-benzimidazolinyl)-piperidine.
  • the intermediate aminoketone (MG 16457, m.p. 158-160°C with dec, as hydrogen oxalate) is prepared from 6-(alpha-bromopropionyl)thiochromane and 4-(2-methyl-1-benzymidazolinyl)-piperidine.
  • EXAMPLE 33 1-( 6-Thiochromanyl )-2-(4-benzamido-1-piperidinyl ) -propanol .
  • the intermediate aminoketone (MG 16449; m.p. 177-179°C) is prepared as in the foregoing Examples starting from 3-(4-piperidinylidene)-indolin-2-one.
  • the following hydrogenation was carried out with diisobutyl aluminum hydride at -20°C in CH 2 Cl 2 under nitrogen.
  • the intermediate aminoketone is prepared starting from 6-pentanoylthiochromane (Cagniant et al., C.R. Soc. Chim. France 223, 1012, 1946) through the alpha-bromoderivative and condensation with 1-cinnamoyl ⁇ iperazine.
  • N-formylpiperazine and 3 g of NaHCO 3 in 200 ml of ethanol is stirred at the boiling temperature for 8 hrs, then 2.6 g of NaBH 4 in 30 ml of water is added and heating is continued for 4 hrs.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

Des dérivés de dihydrobenzothiophène et de thiochromane ont la formule générale (I). Ces composés combattent l'hypertension, inhibent l'agrégation des plaquettes et présentent une activité hypolipidémiante, spasmolytique antianoxique, anti-coagulante, antagoniste du calcium et neuroleptique.
PCT/EP1986/000607 1985-10-14 1986-09-29 Aminoalcools de dihydrobenzothiophene et de thiochromane WO1987002359A1 (fr)

Priority Applications (3)

Application Number Priority Date Filing Date Title
DK297887A DK297887A (da) 1985-10-14 1987-06-11 Dihydrobenzothiophen- og thiochroman-aminoalkoholer
NO872468A NO872468L (no) 1985-10-14 1987-06-12 Dihydrobenzotiofen og tiokromanaminoalkoholer.
KR870700499A KR870700621A (ko) 1985-10-14 1987-06-12 디하이드로 벤조티오펜 및 티오크로만 아미노알코올

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
GB8525256 1985-10-14
GB858525256A GB8525256D0 (en) 1985-10-14 1985-10-14 Dihydrobenzothiophene & thiochromane amino-alcohols
GB8615562 1986-06-25
GB868615562A GB8615562D0 (en) 1986-06-25 1986-06-25 Aminoalcohols

Publications (1)

Publication Number Publication Date
WO1987002359A1 true WO1987002359A1 (fr) 1987-04-23

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Application Number Title Priority Date Filing Date
PCT/EP1986/000607 WO1987002359A1 (fr) 1985-10-14 1986-09-29 Aminoalcools de dihydrobenzothiophene et de thiochromane

Country Status (6)

Country Link
US (1) US4902799A (fr)
KR (1) KR870700621A (fr)
AU (1) AU6548486A (fr)
DK (1) DK297887A (fr)
GR (1) GR862525B (fr)
WO (1) WO1987002359A1 (fr)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009026227A2 (fr) * 2007-08-16 2009-02-26 The University Of Mississippi Ligands de récepteur sigma hautement sélectifs
US8686008B2 (en) 2007-08-16 2014-04-01 The University Of Mississippi Highly selective sigma receptor ligands
US9604926B2 (en) 2007-08-16 2017-03-28 The University Of Mississippi Highly selective sigma receptor radioligands

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1992003131A1 (fr) * 1990-08-13 1992-03-05 G.D. Searle & Co. Utilisation de composes d'aminoalcools heterocycliques dans le traitement d'affections du systeme nerveux central
JPWO2008044632A1 (ja) * 2006-10-06 2010-02-12 大正製薬株式会社 １−ナフチルアルキルピペリジン誘導体

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3928358A (en) * 1973-05-21 1975-12-23 Boehringer Sohn Ingelheim Piperazine derivatives
FR2370472A2 (fr) * 1976-11-10 1978-06-09 Continental Pharma Amino-alcool heterocyclique, son sel et son procede de preparation

Family Cites Families (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4246268A (en) * 1979-02-09 1981-01-20 Richardson-Merrell Inc. Neuroleptic-4-(naphthylmethyl)piperidine derivatives
FR2469411A1 (fr) * 1979-11-15 1981-05-22 Science Union & Cie Nouveaux derives de la piperidylbenzimidazolinone, leurs procedes de preparation et les compositions pharmaceutiques les renfermant
CA1183847A (fr) * 1981-10-01 1985-03-12 Georges Van Daele N-(3-hydroxy-4-piperidinyl)benzamide; derives
JPS58180481A (ja) * 1982-04-15 1983-10-21 Kyowa Hakko Kogyo Co Ltd 新規なピペリジン誘導体
JPS60100542A (ja) * 1983-11-07 1985-06-04 Otsuka Pharmaceut Factory Inc １，４，５，８−テトラアルコキシナフタレン誘導体
US4552965A (en) * 1984-07-31 1985-11-12 University Of California 2α, 3β, 4aβ, 8aα-Decahydro-3-(4-phenyl-1-piperidinyl)-2-naphthalenol

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3928358A (en) * 1973-05-21 1975-12-23 Boehringer Sohn Ingelheim Piperazine derivatives
FR2370472A2 (fr) * 1976-11-10 1978-06-09 Continental Pharma Amino-alcool heterocyclique, son sel et son procede de preparation

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
CHEMICAL ABSTRACTS, Volume 87, No. 19, 7 November 1977, Columbus, Ohio (US) N. HIROSE et al.: "Synthesis and Psychotropic Activity of some 5-(w-(4-Arylpiperazin-1-yl)Alkanoyl)-2,3-Dihydrobenzofurans and Related Compounds", see page 588, column 152125d, & Yakugaku Zassi 1977, 97(5), 540-52 (Japan) *

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009026227A2 (fr) * 2007-08-16 2009-02-26 The University Of Mississippi Ligands de récepteur sigma hautement sélectifs
WO2009026227A3 (fr) * 2007-08-16 2009-04-09 Univ Mississippi Ligands de récepteur sigma hautement sélectifs
US8686008B2 (en) 2007-08-16 2014-04-01 The University Of Mississippi Highly selective sigma receptor ligands
US8809381B2 (en) 2007-08-16 2014-08-19 The University Of Mississippi Highly selective sigma receptor ligands
US9604926B2 (en) 2007-08-16 2017-03-28 The University Of Mississippi Highly selective sigma receptor radioligands

Also Published As

Publication number Publication date
KR870700621A (ko) 1987-12-30
DK297887D0 (da) 1987-06-11
US4902799A (en) 1990-02-20
DK297887A (da) 1987-06-11
AU6548486A (en) 1987-05-05
GR862525B (en) 1987-02-09

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